(1) Field of the Invention
The present invention relates to a drug delivery system, and, more particularly, to a pulsatile drug delivery system for diltiazem HCl capable of site-specific delivery and pulsatile (bolus) kinetics.
(2) Description of the Prior Art
Several investigators have developed pulsatile drug delivery systems that provide slow and/or fast release of a drug based upon physical conditions such as pH, temperature, ionic strength, glucose concentration of metabolites (U.S. Pat. No. 5,226,902); use expandable core material that can be released at specific sites over a period of time (U.S. Pat. No. 4,649,043); or employ an orificed wall constructed of an elastomer that stretches under pressure as osmotic infusion progresses (U.S. Pat. No. 5,221,278).
Publications report development of programmable pulsatile drug delivery systems from an erodible association polymer system and a multi-laminate sample design with alternating drug-loaded layers that deliver a drug only when and where it is needed, at the minimum dose level required to elicit therapeutic results. (Pharmaceutical Research, Vol. 16, No. 8, 1993. "Programmable Drug Delivery from an Erodible Association Polymer System", Xin Xu and Ping I. Lee.) Other report use of hydrophobic material and surfactant that allows for rapid drug release after a predetermined lag time, (Journal of Controlled Release, Vol. 31 1994, 99-108. "The Time Clock System: a New Oral Dosage Form for Fast and Complete Release of Drug after a Predetermined Time", F. Pozzi, P. Furlani, A. Gazzaniga, S. S. Davis, I. R. Wilding.)
Still others report that, by varying the thickness of the film, drug release after the lag period can be enhanced by electrostatic or other physiochemical interactions between the polymer and organic acids.
These investigators have included organic acids such as succinic acid, in order to design a drug delivery system that provides pulsatile kinetics of drug release. (Pharmaceutical Research, Vol. 11, No. 1, 1994, "An Organic Acid-Induced Sigmoidal Release System for Oral Controlled-Release Preparations", S. Narisawa, M. Nagata, C. Danyoshi, H. Yoshino, K. Murata, Y. Hirakawa, and K. Noda.) However, the use of such gastro-irritants and the chronic exposure of the gastric mucosa to such materials can create a potential for mucosal damage.
Several patents have been granted with regard to a controlled release diltiazem formulation for once-a-day dosage--e.g. U.S. Pat. No. 4,894,240, No. 5,286,497, and No. 5,364,620.
All of these patents describe the use of extraneous insolubles in the diltiazem core. These insolubles include organic acids such as fumaric acid, succinic acid, malic acid and adipic acid, as well as lubricants such as talc, sodium stearate, magnesium stearate, and stearic acid. The presence of the organic acids can have a deliterious effect in the gastrointestal tract. Additionally, the controlled release formulation did not permit efficacious drug delivery while providing rate-controlled delivery of drug molecules at the site of absorption in the G.I. Tract.